This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. BACKGROUND: HIV-infected individuals rely on antiretroviral therapy (ART) to control viral replication. Despite abundant demonstrable benefits, the multiple limitations of ART point to the potential advantages of therapeutic vaccination approaches that could provide sustained host control of viral replication after discontinuation of ART. We provide evidence from a non-human primate model that a therapeutic vaccine applied to the tonsils can maintain low viral loads after cessation of ART. METHODOLOGY/PRINCIPAL FINDINGS: Animals received 40 weeks of ART initiated 9 weeks after rectal SIVmac239 infection. During ART, animals were vaccinated (or not) with AT-2 inactivated SIVmac239 using CpG-C ISS-ODN (C274) or polyICLC as adjuvants. PolyICLC/AT-2 SIV vaccinated animals maintained viral loads 3[unreadable]10(3) copies/ml for up to 16 weeks post-ART, whereas the C274/AT-2 SIV vaccinated and non-vaccinated animals'viremia ranged between 1[unreadable]10(4)-4[unreadable]10(5) copies/ml (p0.03). Neutralizing Ab activity in plasma was increased by polyICLC/AT-2 tonsillar vaccination under ART, compared to controls (p0.03). Subsequent vaccination of all animals with polyICLC/AT-2 SIV in the absence of ART did not alter viral loads. Other immune parameters measured in blood and tissues were comparable between groups. CONCLUSIONS/SIGNIFICANCE: These results provide support for the potential benefit of mucosally delivered vaccines in therapeutic immunization strategies for control of AIDS virus infection.